1. Field of the Invention
This invention relates to a process for the preparation of highly monodispersed polymeric hydrophilic nanoparticles with or without target molecules encapsulated therein and having sizes of up to 100 nm and a high monodispersity.
2. Description of the Related Art
Following an administration of a drug in a living system the active substance is distributed throughout the body as a function of its physicochemical properties and molecular structure. The final amount of drug reaching its target site may only be a small fraction of the administered dose. Accumulation of drug at the non-targeted site may lead to adverse effect and undesirable side reactions. Therefore, targeting of drug to specific body sites is necessary.
One way of modifying the biodistribution of drugs in the body is to entrap them in ultrafine drug carriers. Among these carriers, liposomes, nanoparticles and pharmacosomes have been extensively studied. The use of liposomes as drug targeting agents is found to be limited due mainly to the problems of low entrapment efficiency, drug instability, rapid drug leakage and poor storage stability. With the aim of overcoming these problems, the production of polymeric nanoparticles has been investigated since the last two decades. Nanoparticles are defined as solid colloidal particles ranging in size from about 10 nm to 1000 nm.
A large number of studies have been reported on recent advances in drug targeting possibilities and sustain release action with nanoparticles encapsulating drugs. In vivo studies have also been reported with special attention to the reticuloendothelial system (RES). Some in vivo studies concerning nanoparticles administration by oral and ocular routes have also been reported in the literature with respect to the possible improvements of bioavailability. These polymeric nanoparticles should be non antigenic, biocompatible and biodegradable.
The important characteristics of the particles used for targeting at specific body sites were found to be influenced mainly by two factors: (i) the size of the nanoparticles and (ii) the surface characteristics of the nanoparticles. Particles smaller than 7 .mu.m and specially nanoparticles are not filtered in the lung and their biodistribution is dependent on their interaction with reticuloendothelial system (RES). Biodegradable nanoparticles are mainly taken up by the Kupffer cells in the liver while small amount of these particles go to macrophages in spleen and bone marrow. Bone marrow uptake and targeting at other sites can be modified drastically by reducing the particle size. Nanoparticles of 200 nm diameter and above have biodistribution dependent on their interaction with RES. The distribution, however, can be reversed if the particle size is made much smaller (i.e. below 100 nm) and particle surfaces are made hydrophilic. As an example, it has been found that if these particles are separated into three size ranges -60 nm, 150 nm and 250 nm and their surfaces are rendered hydrophilic by adsorbing poloxamer type of surfactants, then the small sized particles with maximum surface hydrophilicity are mostly taken up by cells other than Kupffer cells and as shown in FIG. 1 of the accompanying drawings. Specifically FIG. 1 shows size dependant uptake of nanoparticles, uncoated and coated with poloxamer surfactant by bone marrow. These small particles in the blood serum do not adsorb serum protein through opsonisation and as a result, their circulation time in blood is considerably increased. Hydrophobic particles are removed from the circulation very rapidly due to opsonisation. Nanometer sized particles with hydrophilic surface remain in blood for longer period of time so that targeting at specific sites may be facilitated.
At present, nanoparticles for drug encapsulation are prepared by methods involving either polymerisation of dispersed monomers or a dispersion of preformed polymers in emulsion in presence of desired drug. The methods known in the art for the preparation of nanoparticles are (i) dispersion polymerisation method, (ii) emulsion polymerisation method, (iii) dispersion of synthetic polymer nanospheres in emulsion, and (iv) interfacial polymerisation technique. In all these methods emulsions of oil-in-water are used and the polymer is formed or dissolved in the oil phase. As a result, the polymeric materials are always hydrophobic because they are to be soluble in oil and the particles formed are nanoparticles of larger size (i.e., above 100 nm) because the average size of the emulsion droplets is mostly 100 nm and above diameter. More over, since the emulsion droplets are highly polydispersed, the nanoparticles formed have broad spectrum size range and these are also highly polydispersed. Thus, in such known processes (i) one cannot prepare nanoparticles of subcolloidal size and (ii) the emulsion medium demands that the polymeric materials should be hydrophobic.